Sexually transmitted infections (STIs) present significant health and economic challenges in all countries and yet are rarely prioritised for coordinated strategic attention. A number of barriers frustrate efforts to take the response to STIs to scale, including insufficient incidence data and disease surveillance, and political resistance to scientifically-proven and often cost-effective interventions and approaches. This paper applies an analytical approach to the global strategy that includes an investigation of 3 domains: process, programmatic, and political. Key questions are proposed to guide exploration of these domains to help identify and address barriers to, and leverage solutions for, policy success.